The synthesis and SAR of novel diarylsulfone 11β-HSD1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.09.097

In this communication, human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11β-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model.

Full text of DOI:10.1016/j.bmcl.2010.09.097

Bioorganic & Medicinal Chemistry Letters 20 (2010) 7071–7075
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The synthesis and SAR of novel diarylsulfone 11b-HSD1 inhibitors
⇑
Xuelei Yan , Zhulun Wang, Athena Sudom, Mario Cardozo, Michael DeGraffenreid, Yongmei Di,
Pingchen Fan, Xiao He, Juan C. Jaen , Marc Labelle à, Jinsong Liu, Ji Ma, Dustin McMinn, Shichang Miao ,
Daqing Sun, Liang Tang, Hua Tu, Stefania Ursu, Nigel Walker, Qiuping Ye, Jay P. Powers
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2010
Revised 15 September 2010
Accepted 16 September 2010
Available online 29 September 2010
In this communication, human 11b-hydroxysteroid dehydrogenase type
1 (11b-HSD1) inhibitory
activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several
highly potent 11b-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25
showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
11b-HSD1
11b-HSD2
Diabetes
Metabolic syndrome
Hydroxysteroid dehydrogenase
Diarylsulfones
Two isozymes, 11b-HSD1 and 11b-HSD2, catalyze the intercon-
version of the active glucocorticoid cortisol and the inactive
glucocorticoid cortisone. In humans, the reductive, NADPH-depen-
dent isozyme 11b-HSD1 is expressed mainly in liver, adipose, and
brain tissue and converts the inactive glucocorticoid cortisone to
active cortisol in a NADPH-dependent fashion.1–4 11b-HSD2 is
expressed predominantly in the kidneys and catalyzes the reverse
conversion. 11b-HSD1 knockout mice are resistant to diet-induced
obesity and show improved hepatic insulin sensitivity and
decreased glycogenolysis. Conversely, animals over-expressing
11b-HSD1 in adipose tissue develop central obesity and are
hyperglycemic and insulin resistant. Pharmacologic inhibition of
11b-HSD1 in animals with type 2 diabetes improved insulin sensi-
tivity.5 These data suggested that selective inhibition of 11b-HSD1
activity may provide a viable treatment for the metabolic syn-
drome and type 2 diabetes.6–12 As a therapeutic target, 11b-HSD1
has attracted a significant amount of attention in the pharmaceu-
tical industry for the last decade.
sulfonamide series, several new central portions were designed
and evaluated. In this communication, we report the successful
structure-based design, synthesis, and evaluation of a novel series
of HSD1 inhibitors based upon a diaryl sulfone replacement for the
arylsulfonamide piperazine core present in 1. These efforts led to
the discovery of potent, selective, and orally bioavailable inhibitors
with excellent efficacy in a cynomolgus monkey ex vivo enzyme
inhibition model.
The target diarylsulfone analogs were prepared as outlined in
Schemes 1–4.14 The synthesis of compounds 2–16, 18–19, 21,
23–31, and 35, is depicted in Scheme 1. The coupling of commer-
cially available aryl halides and thiophenol in the presence of
cesium carbonate in DMF, followed by Friedel–Crafts acylation at
CF3
O
HO
R
Y
N
NH2
N
S
S
O
O
X
O
O
Our group has published several communications on 11b-HSD1
inhibitors.13 We previously described arylsulfonyl piperazine 1
(Fig. 1) as a potent inhibitor of 11b-HSD1 in biochemical and cellu-
lar assays, with efficacy in an ex vivo pharmacodynamic assay. In
an effort to improve the pharmacokinetic (PK) properties of this
2-35 (Tables 1-5)
1
hHSD1 IC50: 0.83 nM
h293 IC50: 7.3 nM
Rat PK :
CL (L/h/Kg): 1.4
MRT (h): 0.8
%F: 41
⇑
Corresponding author. Tel.: +1 650 244 2237.
E-mail address: xueleiy@amgen.com (X. Yan).
Present address: ChemoCentryx, Inc., Mountain View, CA 94043, USA.
Present address: ML Pharma Consulting, Chatham, New Jersey, USA.
à
Figure 1. 11b-HSD1 inhibitors.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.09.097

7072
X. Yan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7071–7075
Y
X
O
O
Y
Y
Y
ii
SH
SH
(F) Cl
S
S
i
F
iii
F
X
X
X
36
iv
CF3
O
HO
HO
Y
Y
Y
Y
v
vi
vii
S
S
S
S
O
O
X
O
O
O
O
O
X
O
X
X
2-8, 13-16, 18-19, 21, 23-31,35
9 (X=Cl, Y=H)
10 (X=Cl, Y=H)
37
Cmpd
Cmpd
7
Cmpd
3
Cmpd
4
Cmpd
Cmpd
6
X
H
Y
F
X
H
Y
H
X
Cl
F
Y
H
H
H
X
Y
X
3-Cl
Et
Y
H
H
X
H
Y
OMe
H
2
8
Me
H
H
5
NO2
CF3
Cl
H
13
14
15
24
30
16
iPr
Cl
Cl
18
tBu
H
C(CH3)2OH
NO2
19
27
CN
H
21
28
23
Cl
Cl Br
CONH
25
CN
26
Cl
NHCONH2
CH2CH2F
NH2
4-pyridyl
Cl 4-CN-Ph
Cl
29
Cl
Cl
31
35
CN
2
Scheme 1. Reagents and conditions: (i) Cs2CO3, DMF, 100 °C; 48–92%; (ii) acetyl chloride, AlBr3, CS2 0 °C, 24–86%; (iii) Cs2CO3, DMF, 100 °C; 37–89%; (iv) mCPBA, CH2Cl2,
69–83%; (v) TMS–CF3, TBAF, THF, 20–75%; (vi) LiMe in Et2O, THF, 0 °C, 54%; (vii) DAST, CH2Cl2, À78 °C, 45%.
Y
Br
O
CF3
O
CHO
ii
HO
CHO
OH
CN
Y
Y
SH
iii
SH
S
S
F
S
i
S
F
Cl
Cl
i, ii
Cl
O
O
O
O
Br
Br
43
42
38
39
CF3
HO
I
iii
Y
iv
X = cyclopropyl Y = H
17
20
34
iv
S
S
X = 4-F-Ph
Y = H
Cl
45
S
Cl
O
O
X = cyclopropyl
Y = CN
X
44
17, 20, 34
Scheme 4. Reagents and conditions: (i) Cs2CO3, DMF, 100 °C; 89%; (ii) NaBH4, 0 °C,
95%; (iii) I2, PPh3, imidazole 70 °C, 20%; (iv) cyclopropanecarbonitrile, n-BuLi,
iPr2NH, THF, À78 °C, 28%.
Scheme 2. Reagents and conditions: (i) Cs2CO3, DMF, 100 °C; 92%; (ii) mCPBA,
CH2Cl2, 90%; (iii) TMS–CF3, TBAF, THF, 59%; (iv) X-B(OH)2, K3PO4, Pd(PPh3)4,
toluene/H2O, 20:1, 100 °C, 35–62%.
tions, followed by oxidation with mCPBA to afford ketone 38.
Phenyl bromide 39 was generated upon treatment of 38 with
TMS–CF3 in THF. The target compounds 17, 20, and 34 were then
obtained by Suzuki coupling of 39 with the appropriate boronic
acids.
Phenyl bromide 39 was also used as the starting material for the
synthesis of analogs 22 (Scheme 3). Stille coupling of 39 with
allyltri-n-butyltin was followed by conversion to aldehyde 41.
Primary amide 22 was produced by further oxidation of 41 with
Jones reagent, followed by amide coupling of the resultant acid
with ammonia.
Scheme 4 shows the synthesis of the intermediate 45 necessary
for making analogs 32 and 33 (Table 4). Accordingly, aldehyde 42,
which was generated by the coupling reaction of 3-chloro-4-fluo-
robenzaldehyde and thiophenol, was reduced to alcohol 43 with
sodium borohydride. Conversion of the alcohol to the iodide fur-
nished 44. Treatment of 44 with cyclopropanecarbonitrile and
LDA in THF gave intermediate 45.
CF3
CF3
HO
HO
ii
i
S
S
O
O
O
O
Br
39
40
CF3
CF3
HO
HO
iii, iv
S
S
O
O
O
O
H
NH2
O
O
41
22
Scheme 3. Reagents and conditions: (i) allyltri-n-butyltin, Pd(PPh3)4, benzene,
100 °C, 96%; (ii) NaIO4, OsO4, MeOH/H2O 1:1, 82%; (iii) Jones reagent, acetone, 72%;
(iv) NH3 in CH2Cl2, EDC, HOBt, CH2Cl2/DMF, 64%.
Compounds were evaluated in vitro for inhibition of human
(h-HSD1) and mouse 11b-HSD1 enzymes, as well as in cell-based
assays (h-293) using our previously published procedures: IC50
values were determined by scintillation proximity assay (SPA);
h-293 = HEK 293 cells stably transfected with full length human
11b-HSD1.13 The results are summarized in Tables 1–5.
In order to establish the minimum pharmacophore required for
11b-HSD1 inhibition, a small focused set of analogs was initially
synthesized. This set demonstrated a steep SAR and, as shown in
Tables 1 and 2-substitution was found to be quite important for
the 4-position with acetylchloride and aluminum tribromide
generated intermediate 36. Oxidation of 36 with mCPBA yielded
sulfone 37. Treatment of 37 with TMS–CF3 in THF at room temper-
ature gave the trifluoromethyl tertiary alcohol in moderate to
excellent yield, while reaction of 37 with methyl lithium gave
tertiary alcohol 9. Analog 10 was obtained by treatment of tertiary
alcohol 9 with DAST in CH2Cl2.
Compounds 17, 20, and 34 were prepared via the route
described in Scheme 2. The coupling reaction of 4-fluoroacetophe-
none with 2-bromothiophenol proceeded under standard condi-

X. Yan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7071–7075
7073
Table 1
Table 3
Inhibition of 11b-HSD1 by selected analogs: initial sulfonamide replacements
Modification to the 2-position of the aryl ring of the right-hand side
CF3
HO
CF3
HO
R
S
S
O
O
O
O
X
h-HSD1a IC50 (nM)
h-293a IC50 (nM)
Compd
R
h-HSD1a IC50 (nM)
h-293 (cell)a IC50 (nM)
Compd
X
2
3
4
5
6
7
8
Ph
79
4.7
4.4
18.1
28.7
36.6
24
355
50
56
317
229
240
233
3
13
4
Cl
F
Me
CF3
Et
iPr
Cyclopropyl
t-Bu
CN
4-F-Ph
C(CH3)2OH
CH2CONH2
4.7
11
50
129
56
145
93
2-Cl–Ph
2-Me-Ph
3-Cl-Ph
4-OMe-Ph
4-F-Ph
4.4
7.5
1.2
4.1
1.2
11
14
15
16
17
18
19
20
21
22
1120
28
4-NO2-Ph
280
315
2410
>300
>300
a
IC50 determined by scintillation proximity assay (SPA). All potency data are
50
reported as means of at least two determinations with variation around the mean
<50%. h-293 = HEK 293 cells stably transfected with full length human 11b-HSD1.
Compounds were tested as racemic mixtures.
109
144
>300
a
All potency data are reported as means of at least two determinations with
variation around the mean <50%. Compounds were tested as racemic mixtures.
Table 2
Inhibition of 11b-HSD1 by selected analogs: modifications of the left-hand aryl ring
Table 4
Ar
S
Inhibition of 11b-HSD1 by selected analogs: modification to the 4-position of the
right-hand aryl ring
O
O
Cl
CF3
HO
Y
Compd
Ar
h-HSD1a IC50 (nM)
h-293a IC50 (nM)
CF3
S
HO
O
O
Cl
3
4.7b
50b
Compd
Y
h-HSD1a,bIC50 (nM)
h-293a IC50 (nM)
HO
F
3
23
24
25
26
27
28
29
30
31
H
Cl
Br
CN
4.7
2
50
43
59
9
10
11
102
30
—
1.8
2.7
3.2
24
7
30
18
86
39
NO2
105
294
110
>300
>300
>300
—
4-CN-Ph
4-Pyridyl
NH2
CONH2
NHCONH2
20
455
CN
32
9
184
Cl
O
12
>300
>3000
33
30
650
NH2
Cl
a
All potency data are reported as means of at least two determinations with
a
All potency data are reported as means of at least two determinations with
variation around the mean <50%. Compounds were tested as racemic mixtures.
variation around the mean <50%.
b
Compound tested as racemic mixtures.
the slightly larger isopropyl (16) and t-butyl (18) groups led to
decrease in activity, especially in the cellular assay. Replacement
of the alkyl group with aryl substitution at C2 position (20) re-
sulted in a significant decrease in activity, suggesting limited space
in this region of the enzymes active site. The introduction of more
polar groups (21 and 22) also resulted in a significant decrease in
potency.
Previously reported structure–activity relationships in the aryl-
sulfonylpiperazine series suggested that the substitution on the
distal nitrogen of the piperazine (1) were well tolerated and gave
compounds with sub-nanomolar inhibitory potency.13 We applied
the same strategy to the diarylsulfone series and made modifica-
tions at the para-position of the aryl ring (Table 4). Incorporation
of a chloro, bromo, or cyano group (23–25) at the para-position
of the aryl ring gave about twofold increase in human biochemical
potency over 3, although the cellular potency remained the same,
while a nitro group (26) led to approximately a twofold reduction
biochemical activity, while the unsubstituted phenyl analog 2 was
significantly less active. Shifting the substitution to meta- and
para-position also led to a drop in activity.
We then turned our attention to modifications on the left-hand
side aryl ring of 3 (Table 2). In this limited set of analogs, replace-
ment of the para-trifluoromethyl carbinol resulted, in varying
degree, in a reduction in potency, consistent with our earlier SAR
in the arylsulfonamide piperazine series.
The improved potency of the 2-substituted analogs prompted
us to further investigate a more diversified set of derivatives
(Table 3). Compound (17), containing a 2-cyclopropyl group, was
found to be the most potent, with an IC50 of 1.2 nM, in the
biochemical assay and 28 nM in the cellular assay, which was a 2
to 3-fold improvement over the parent (2-chloro) compound 3.
The 2-ethyl analog (15) gave a modest threefold improvement in
biochemical potency but a twofold loss in cellular potency, while

7074
X. Yan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7071–7075
Table 5
Mesenteric fat 11β-HSD1 activity
Inhibition of 11b-HSD1 by selected analogs: effect of absolute stereochemistry at the
trifluoromethylcarbinol moiety
4
3
2
1
0
CF3
HO
Y
S
O
O
X
a
Compd
X
Y
h-HSD1 IC50 (nM)
h-293a IC50 (nM)
(R)-25
(S)-25
(R)-34
(S)-34
(R)-35
(S)-35
Cl
Cl
CN
CN
CN
CN
CN
CN
14
165
11
125
2.6
376
20.7
0.9
11.2
0.6
36
Cyclopropyl
Cyclopropyl
CH2CH2F
CH2CH2F
1.2
0
2
10
a
All potency data are reported as means of at least two determinations with
mg/Kg
variation around the mean <50%.
Figure 2. Ex vivo 11b-HSD1 enzyme activity in intact mesenteric fat collected from
cynomolgus monkeys dosed orally with (S)-25. Plasma and mesenteric fat samples
were collected 2 h after compound was administered orally in dosing vehicle (1%
methylcellulose and 1% Tween 80 in sterile water). 11b-HSD1 enzyme activity was
measured as the [3H]-cortisol formed after 1 h incubation of fat samples at 37 °C in
reaction buffer containing [3H]-cortisone. Compound concentration in plasma and
fat samples was determined by LC/MS/MS.
Table 6
Pharmacokinetic profiles of compound (S)-25
CF3
HO
CN
S
O
O
Cl
Species CL (iv, L/h/Kg) AUC (po, Vdss (iv, L/Kg) MRT (iv, h) F (po, %)
g h/L)
l
Rata,b
0.49
0.02
1815
33,800
630
3.0
1.7
1.4
7.2
100
6.5
55
73
13
Doga,b
Cynoa,b 0.43
a
Dosed iv 0.5 mg/kg, po 2.0 mg/kg.
Values are an average for three rats, dogs and monkeys.
b
in cellular potency. Aryl derivatives (27 and 28) had a 4 to 5-fold
decrease in potency over the parent compound 3. The introduction
of more polar solubilizing groups (29–31) resulted in substantial
loss of activity. We also modified the para-position with other
solubilizing groups identified in our previous studies, such as the
moiety from inhibitor 1 (33). In this case, such replacement led
to a significant decrease in potency.
As observed in our previously reported trifluoromethylcarbinol
containing analogs, the (S) configuration proved to have greater
11b-HSD1 inhibitory activity.13 In the diarylsulfone series, the
two enantiomers were also separated and their absolute configura-
tions were determined by single crystal small molecule X-ray
crystallography. As predicted from our earlier work, the (S)-enanti-
omers were found to be about 20 to 40 times more potent than the
corresponding (R)-isomers in both the biochemical and cellular as-
says (Table 5).
Figure 3. Co-crystal structure of compound (S)-35 in human 11b-HSD1. The protein
is shown in both stick and molecular surface representations which are color coded
(red for oxygen atoms, blue for nitrogen, orange for sulfur, and wheat for carbon).
The inhibitor and the cofactor NADP+ are shown in sticks and color coded gray for
carbon atoms in NADP+ and green for the inhibitor. (PDB code: 3OQ1).
duction in mesenteric fat (Fig 2). These results demonstrate that
(S)-25 was effective in lowering 11b-HSD1 adipose activity in
non-human primates when administered orally.
The structure of a representative diarylsulfone inhibitor bound
to human 11b-HSD1 was determined by X-ray crystallography
(Fig 3). The co-crystal structure of compound (S)-35 with human
11b-HSD1 revealed that the inhibitor binds to the substrate site
in a V-shape with its trifluoromethylcarbinol group pointing
towards the cofactor NADP+ site. The central sulfonyl group makes
a hydrogen bond from one of its oxygen atom to the backbone
amide of Ala172, as well as Van der Waals contacts with Ser170
in the catalytic site.
In summary, we have developed a novel series of highly potent
and selective 11b-HSD1 inhibitors (in all cases 11b-HSD2 IC50
>10 lM) with a diarylsulfonyl scaffold. The most potent inhibitors
had sub-nanomolar IC50 values in the human biochemical assay
and IC50 value <5 nM in the cellular assay. Representative com-
pound (S)-25 also had low clearance and excellent oral bioavail-
ability (>50%) in both rats and dogs. Compound (S)-25 was
Pharmacokinetic data for (S)-25 is presented in Table 6. With
the novel sulfone center core, (S)-25 exhibited a significant
improvement of in vivo metabolic stability and oral bioavailability
compared to 1.
In addition to the excellent potency and pharmacokinetic
profile of (S)-25, this molecule had suitable activity against the
cynomolgus monkey 11b-HSD1 enzyme (IC50 = 3 nM) and was
selected for further evaluation in a cynomolgus monkey ex vivo
pharmacodynamic model. In this study, cynomolgus monkeys
were dosed orally with 2 and 10 mg/kg of inhibitor (S)-25. At 2 h
post-dose, samples of mesenteric fat tissue were taken. Following
1 h incubation of these tissues in media containing [3H]-cortisone,
11b-HSD1 activity was measured through detection of tritiated
cortisol levels using a scintillation proximity assay.13 Relative to
controls, all dose groups showed a decrease in [3H]-cortisol pro-

X. Yan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7071–7075
7075
10. Xiang, J.; Ipek, M.; Suri, V.; Massefski, W.; Pan, N.; Ge, Y.; Tam, M.; Xing, Y.;
Tobin, J. F.; Xu, X.; Tam, S. Bioorg. Med. Chem. Lett. 2005, 15, 2865.
11. Coppola, G. M.; Kukkola, P. J.; Stanton, J. L.; Neubert, A. D.; Marcopulos, N.; Bilci,
N. A.; Wang, H.; Tomaselli, H. C.; Tan, J.; Aicher, T. D.; Knorr, D. C.; Jeng, A. Y.;
Dardik, B.; Chatelain, R. E. J. Med. Chem. 2005, 48, 6696.
12. (a) Yeh, V. S. C.; Patel, J. R.; Yong, H.; Kurukulasuriya, R.; Fung, S.; Monzon, K.;
Chiou, W.; Wang, J.; Stolarik, D.; Imade, H.; Beno, D.; Brune, M.; Jacobson, P.;
Sham, H.; Link, J. T. Bioorg. Med. Chem. Lett. 2006, 16, 5414; (b) Yeh, V. S. C.;
Kurukulasuriya, R.; Madar, D.; Patel, J. R.; Fung, S.; Monzon, K.; Chiou, W.;
Wang, J.; Jacobson, P.; Sham, H. L.; Link, J. T. Bioorg. Med. Chem. Lett. 2006, 16,
5408; (c) Yeh, V. S. C.; Kurukulasuriya, R.; Fung, S.; Monzon, K.; Chiou, W.;
Wang, J.; Stolarik, D.; Imade, H.; Shapiro, R.; Knourek-Segel, V.; Bush, E.;
Wilcox, D.; Nguyen, P. T.; Brune, M.; Jacobson, P.; Link, J. T. Bioorg. Med. Chem.
Lett. 2006, 16, 5555; (d) St. Jean, D. J., Jr.; Yuan, C.; Bercot, E. A.; Cupples, R.;
Chen, M.; Fretland, J.; Hale, C.; Hungate, R. W.; Komorowski, R.; Veniant, M.;
Wang, M.; Zhang, X.; Fotsch, C. J. Med. Chem. 2007, 50, 429.
selected for evaluation in a non-human primate ex vivo model and
showed good efficacy when administered orally. Finally, X-ray
co-crystallographic data of (S)-35 with 11b-HSD1 revealed several
key interactions for the inhibitor binding. Further investigation of
the diarylsulfone class 11b-HSD1 inhibitors will be reported in
due course.
References and notes
1. Draper, N.; Stewart, P. M. J. Endocrinol. 2005, 186, 251.
2. Thieringer, R.; Hermanowski-Vosatka, A. Expert Rev. Cardiovasc. Ther. 2005, 3,
911.
3. Morton, N. M.; Paterson, J. M.; Masuzaki, H.; Holmes, M. C.; Staels, B.; Fievet, C.;
Walker, B. R.; Flier, J. S.; Mullins, J. J.; Seckl, J. R. Diabetes 2004, 53, 931.
4. Tomlinson, J. W.; Walker, E. A.; Bujalska, I. J.; Draper, N.; Lavery, G. G.; Cooper,
M. S.; Hewison, M.; Stewart, P. M. Endocr. Rev. 2004, 25, 831.
13. (a) Julian, L. D.; Wang, Z.; Bostick, T.; Caille, S.; Choi, R.; DeGraffenreid, M.; Di,
Y.; He, X.; Hungate, R. W.; Jaen, J. C.; Liu, J.; Monshouwer, M.; McMinn, D.; Rew,
Y.; Sudom, A.; Sun, D.; Tu, H.; Ursu, S.; Walker, N.; Yan, X.; Ye, Q.; Powers, J. P. J.
Med. Chem. 2008, 51, 3953; (b) Sun, D.; Wang, Z.; Di, Y.; Jaen, J. C.; Labelle, M.;
Ma, J.; Miao, S.; Sudom, A.; Tang, L.; Tomooka, C. S.; Tu, H.; Ursu, S.; Walker, N.;
Yan, X.; Ye, Q.; Powers, J. P. Bioorg. Med. Chem. Lett. 2008, 18, 3513; (c) Rew, Y.;
McMinn, D. L.; Wang, Z.; He, X.; Hungate, R. W.; Jaen, J. C.; Sudom, A.; Sun, D.;
Tu, H.; Ursu, S.; Villemure, E.; Walker, N. P. C.; Yan, X.; Ye, Q.; Powers, J. P.
Bioorg. Med. Chem. Lett. 2009, 19, 1797; (d) McMinn, D. L.; Rew, Y.; Wang, Z.;
Sudom, A.; Caille, S.; DeGraffenreid, M.; He, X.; Hungate, R.; Jiang, B.; Jaen, J.;
Julian, L. D.; Kaizerman, J.; Novak, P.; Sun, D.; Tu, H.; Ursu, S.; Walker, N. P. C.;
Yan, X.; Ye, Q.; Wang, Z.; Powers, J. P. Bioorg. Med. Chem. Lett. 2009, 19, 1446;
(e) Sun, D.; Wang, Z.; Cardozo, M.; Choi, R.; DeGraffenreid, M.; Di, Y.; He, X.;
Jaen, J. C.; Labelle, M.; Liu, J.; Ma, J.; Miao, S.; Sudom, A.; Tang, L.; Tu, H.; Ursu,
S.; Walker, N.; Yan, X.; Ye, Q.; Powers, J. P. Bioorg. Med. Chem. Lett. 2009, 19,
1522.
5. Wang, M. Curr. Opin. Invest. Drugs 2006, 7, 319.
6. Barf, T.; Vallgarda, J.; Emond, R.; Haggstrom, C.; Kurz, G.; Nygren, A.; Larwood,
V.; Mosialou, E.; Axelsson, K.; Olsson, R.; Engblom, L.; Edling, N.; Ronquist-Nii,
Y.; Ohman, B.; Alberts, P.; Abrahmsen, L. J. Med. Chem. 2002, 45, 3813.
7. Hermanowski-Vosatka, A.; Balkovec, J. M.; Cheng, K.; Chen, H. Y.; Hernandez,
M.; Koo, G. C.; Le Grand, C. B.; Li, Z.; Metzger, J. M.; Mundt, S. S.; Noonan, H.;
Nunes, C. N.; Olson, S. H.; Pikounis, B.; Ren, N.; Robertson, N.; Schaeffer, J. M.;
Shah, K.; Springer, M. S.; Strack, A. M.; Strowski, M.; Wu, K.; Wu, T.; Xiao, J.;
Zhang, B. B.; Wright, S. D.; Thieringer, R. J. Exp. Med. 2005, 202, 517.
8. Olson, S.; Aster, S. D.; Brown, K.; Carbin, L.; Graham, D. W.; Hermanowski-
Vosatka, A.; LeGrand, C. B.; Mundt, S. S.; Robbins, M. A.; Schaeffer, J. M.;
Slossberg, L. H.; Szymonifka, M. J.; Thieringer, R.; Wright, S. D.; Balkovec, J. M.
Bioorg. Med. Chem. Lett. 2005, 15, 4359.
9. Gu, X.; Dragovic, J.; Koo, G. C.; Koprak, S. L.; LeGrand, C. B.; Mundt, S. S.; Shah,
K.; Springer, M. S.; Tan, E. Y.; Thieringer, R.; Hermanowski-Vosatka, A.; Zokian,
H. J.; Balkovec, J. M.; Waddell, S. T. Bioorg. Med. Chem. Lett. 2005, 15, 5266.
14. All compounds gave satisfactory 1H NMR, HPLC, and MS data in full agreement
with their proposed structures.